Haemophilia A - In pursuit of optimised outcomes via personalised treatment

Research output: ThesisDoctoral Thesis (compilation)

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Abstract

Haemophilia A (HA) is a hereditary bleeding disorder, characterised by deficiency of coagulation factor VIII (FVIII). Repeated joint bleeds can lead to permanent joint damage. FVIII replacement therapy has a high cost and can reduce but not completely prevent bleeding. This thesis aims to promote personalised treatment and optimised outcomes through a clinical and pharmacokinetic characterisation. Paper I compared the PK estimations by two population-PK tools, MyPKFiT and WAPPS-Hemo, in a cohort of male patients with severe HA treated with octocog alfa. Both web tools were able to overcome assay discrepancy and produced similar FVIII half-life estimations. However, WAPPS-Hemo generated significantly longer estimations of time to various FVIII trough levels, and as a result, significantly lower dosing proposals than MyPKFiT, with possible clinical implications. Paper II investigated a cohort of patients with severe and moderate HA in Malmö and Oslo, after the switch from standard half-life (SHL) FVIII products to BAY 81-8973. The median annualised bleeding rate was 0 before and after the switch, despite the presence of arthropathy and mostly intermediate intensity dose regimens. Treatment adherence was excellent. The Oslo centre had significantly lower annual FVIII consumption. We concluded that personalised prophylaxis and good adherence can reduce FVIII consumption and maintain haemostatic efficacy. Paper III investigated the underlying reasons for the difference in FVIII consumption between the Malmö and Oslo cohorts in Paper II. This analysis showed that most patients in Oslo were on secondary prophylaxis with intermediate dose intensity, whereas most patients in Malmö were on primary prophylaxis. Secondary prophylaxis prevents bleeds but at a cost of more arthropathy and reduced health-related quality of life, compared to higher intensity primary prophylaxis. Additionally, non-null F8 genotypes may allow lower factor consumption with similar haemophilia joint health score (HJHS) and bleeding rates, compared to null genotypes. In Paper IV, the long-term joint outcomes, bleeding phenotype, and prophylaxis implementation in childhood were examined in patients born after 1980, with severe HA on primary prophylaxis. This study showed that primary prophylaxis is effective in delaying but does not completely prevent the gradual development of arthropathy in severe HA, with total HJHS rising to a median of 4 at 35-40 years. We concluded that joint assessments should begin at an early age and prophylaxis escalation should proceed expeditiously to prevent bleeds.
Translated title of the contributionHemofili A: Jakten att uppnå optimerade resultat genom personaliserad behandling
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Translational Medicine
Supervisors/Advisors
  • Astermark, Jan, Supervisor
  • Berntorp, Erik, Assistant supervisor
  • Gretenkort Andersson, Nadine, Supervisor
Award date2024 May 3
Place of PublicationLund
Publisher
ISBN (Print) 978-91-8021-549-7
Publication statusPublished - 2024

Bibliographical note

Defence details
Date: 2024-05-03
Time: 09:00
Place: Kvinnoklinikens aula, Jan Waldenströms gata 47, Skånes Universitetssjukhus i Malmö.
External reviewer(s)
Name: Lambert, Catherine
Title: professor
Affiliation: Cliniques Universitaires Saint-Luc, Brussels

Subject classification (UKÄ)

  • Hematology

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